US2024092942A1PendingUtilityA1

Trimeric polypeptides and uses thereof in the treatment of cancer

41
Individually held — no corporate assignee on recordPriority: Mar 5, 2021Filed: Mar 7, 2022Published: Mar 21, 2024
Est. expiryMar 5, 2041(~14.6 yrs left)· nominal 20-yr term from priority
Inventors:Luis Álvarez VallinaMarta Compte Grau
C07K 16/468A61P 35/00C07K 16/2863C07K 16/2878A61K 2039/507A61K 2039/505C07K 2317/31C07K 2317/622C07K 2317/626C07K 2317/569C07K 2319/00
41
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Claims

Abstract

The invention relates to trimeric polypeptide complex comprising three monomer polypeptides wherein each monomer polypeptide comprises an anti-4-1BB specific agonistic single-chain antibody fragment (scFv), a homotrimerization domain and a polypeptide region which is capable of specifically binding to a tumor associated antigen. The invention also relates to said trimeric polypeptide complexes for use in the treatment of cancer.

Claims

exact text as granted — not AI-modified
1 . A trimeric polypeptide complex comprising three monomer polypeptides wherein each monomer polypeptide comprises:
 a) An anti-4-1BB specific agonistic single-chain antibody fragment (scFv) wherein the V H  domain is N-terminal to the V L  domain,   b) a homotrimerization domain selected from the group consisting of the collagen XVIII homotrimerization domain (TIE XVIII ), the collagen XV homotrimerization domain (TIE XV ) and a functionally equivalent variant thereof, and   c) a polypeptide region which is capable of specifically binding to a tumor associated antigen.   
     
     
         2 . A trimeric polypeptide complex comprising three monomer polypeptides wherein each monomer polypeptide comprises:
 a) An anti-4-1BB specific agonistic single-chain antibody fragment (scFv) wherein the CDRs comprise the sequences set forth in SEQ ID NO: 1 or SEQ ID NO: 42, SEQ ID NO: 2 or SEQ ID NO: 43, SEQ ID NO: 3 or SEQ ID NO: 44, SEQ ID NO: 4 or SEQ ID NO: 45, SEQ ID NO: 5 or SEQ ID NO: 46 and SEQ ID NO: 6 or a functionally equivalent variants thereof,   b) a homotrimerization domain selected from the group consisting of the collagen XVIII homotrimerization domain (TIE XVIII ), the collagen XV homotrimerization domain (TIE XV ) and a functionally equivalent variant thereof, and   c) a polypeptide region which is capable of specifically binding to a tumor associated antigen.   
     
     
         3 . The trimeric polypeptide complex according to  claims 1  or  2 , wherein the anti-4-1 BB specific agonistic scFv is humanized or displays a humanized VL domain and/or a partially humanized VH domain. 
     
     
         4 . The trimeric polypeptide complex according to  claim 3  wherein the anti-4-1BB agonistic scFv comprises the sequence set forth in SEQ ID NO: 19. 
     
     
         5 . The trimeric polypeptide according to any of  claims 1  to  4  wherein the region which is capable of specifically binding to the tumor associated antigen is positioned C-terminal with respect to the homotrimerization domain. 
     
     
         6 . The trimeric polypeptide complex according to any one of  claims 1  to  5 , wherein the tumor associated antigen is EGFR. 
     
     
         7 . The trimeric polypeptide complex according to  claim 6  wherein the polypeptide region which is capable of specifically binding to EGFR is an antibody. 
     
     
         8 . The trimeric polypeptide complex according to  claim 7 , wherein the anti-EGFR antibody is a humanized anti-EGFR (huEGFR) single-domain antibody (VHH). 
     
     
         9 . The trimeric polypeptide complex according to  claim 8  wherein the humanized anti-EGFR (huEGFR) single-domain antibody (VHH) comprises the sequence set forth in SEQ ID NO: 28. 
     
     
         10 . The trimeric polypeptide complex according to any one of  claims 1  to  9 , wherein the anti-4-1BB agonistic single-chain antibody fragment (scFv), the homotrimerization domain and/or the region which is capable of specifically binding to the tumor associated antigen are either directly linked or linked through a spacer. 
     
     
         11 . The trimeric polypeptide according to  claim 10  wherein the spacer is a flexible linker with between 1 and 18 residues. 
     
     
         12 . The trimeric polypeptide according to any one of  claims 1  to  11  wherein at least one of the monomers further comprises a tag suitable for detection and/or purification of the trimeric polypeptide. 
     
     
         13 . The trimeric polypeptide according to  claim 1  or  2  wherein the monomer polypeptide comprises the sequence set forth in SEQ ID NO or SEQ ID NO: 
     
     
         14 . A polynucleotide encoding at least one monomer polypeptide forming part of the trimeric polypeptide as defined in any of  claims 1  to  13 . 
     
     
         15 . The polynucleotide according to  claim 14  comprising the sequence set forth in SEQ ID NO: or SEQ ID NO: 
     
     
         16 . A vector comprising a polynucleotide according to any one of  claims 14  or  15 . 
     
     
         17 . A host cell comprising a vector according to  claim 16 . 
     
     
         18 . A combination comprising the trimeric polypeptide according to any of  claims 1  to  13 , the polynucleotide according to any of  claims 14  or  15 , the vector according to  claim 16  or the host cell according to  claim 17  and an immune checkpoint blocker. 
     
     
         19 . The combination according to  claim 18  wherein the immune checkpoint blocker is a PD-L1 inhibitor. 
     
     
         20 . The combination according to  claim 19 , wherein the PD-L1 inhibitor is a PD-L1 antibody. 
     
     
         21 . The combination according to  claim 20 , wherein the PD-L1 antibody is selected from the group consisting of atezolizumab, avelumab and durvalumab. 
     
     
         22 . The combination according to  claim 18 , wherein the immune checkpoint blocker is a PD-1 inhibitor. 
     
     
         23 . The combination according to  claim 22  wherein the PD-1 inhibitor is pembrolizumab or nivolumab. 
     
     
         24 . A pharmaceutical composition comprising a trimeric polypeptide according to any one of  claims 1  to  13 , the polynucleotide according to any of  claims 14  or  15 , the vector according to  claim 16 , the host cell according to  claim 17  or the combination according to any one of  claims 18 - 23  and a pharmaceutical acceptable excipient. 
     
     
         25 . A trimeric polypeptide according to any one of  claims 1  to  13 , the polynucleotide according to any of  claims 14  or  15 , the vector according to  claim 16 , the host cell according to  claim 17 , the combination according to any one of  claims 18 - 23  or the pharmaceutical composition according to  claim 24  for use in the treatment of cancer. 
     
     
         26 . The trimeric polypeptide, the polynucleotide, the vector, the host cell, the combination, or the pharmaceutical composition for use according to  claim 25  wherein the cancer is EGFR positive. 
     
     
         27 . The trimeric polypeptide, the polynucleotide, the vector, the host cell, the combination, or the pharmaceutical composition for use according to  claim 26 , wherein the cancer is selected from the group consisting of colorectal cancer, breast cancer, pancreatic cancer, thyroid cancer, prostate, ovary, head and neck and lung cancer. 
     
     
         28 . The trimeric polypeptide, the polynucleotide, the vector, the host cell, the combination, or the pharmaceutical composition for use according to  claim 27  wherein the breast cancer is triple-negative breast cancer and the lung cancer is small-cell lung cancer.

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